The present invention relates to diastereoselective Michael addition using zinc-amine complex reagent. and further provides a method for the diastereoselective preparation of xcex1-hydroxyacetic acids.
U.S. Pat. No. 5,948,791 discloses fluorine-containing 1,4-disubstituted piperidine derivatives. These compounds are muscarinic M3 receptor antagonists useful for the treatment or prophylaxis of respiratory diseases such as chronic obstructive pulmonary diseases, chronic bronchitis, asthma and rhinitis; digestive diseases such as irritable bowel syndrome, convulsive colitis, diverticulitis and pain accompanying contraction of smooth muscles of the digestive system; urinary disorders like urinary incontinence and frequency in neurogenic pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm and chronic cystisis; and motion sickness.
Many of the derivatives exemplified in U.S. Pat. No. 5,948,792 are of the formula (A) 
where RX is defined in the patent as R2. Their synthesis requires the common precursor (2R)-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid, which may be prepared according to the methods disclosed in U.S. Pat. No. 5,948,792 and summarized in the following scheme: 
The Michael addition of a dioxolanone to a cyclopentenone is the key step in defining the stereochemistry of the phenylacetic acid precursor. The methods described in U.S. Pat. No. 5,948,792 are not suitable for large-scale preparation of the chiral phenylacetic acidxe2x80x94the use of the chiral tricyclic ketone is prohibitively expensive and involves flash pyrolysis requiring specialized equipment, and deprotonation of cyclopentenone using lithium diisopropylamide (LDA) in hexamethylphosphoramide (HMPA) does not impart diastereocontrol to the Michael addition. There is therefore the need for an efficient and stereoselective process amenable to large-scale production to provide the phenylacetic acid precursor of the desired stereochemistry.
The present invention provides a process for the diastereoselective preparation of Michael adducts of a cycloalkenone and a chiral 2,5-disubstituted-1,3-dioxolan-4-one using a zinc-amine complex and the free amine of the zinc-amine complex. The novel process comprises the steps of:
(a) contacting said chiral 2,5-disubstituted-1,3-dioxolan-4-one with a base to provide the corresponding enolate;
(b) contacting said enolate with a zinc-amine complex followed by addition of the free amine component of the zinc-amine complex;
(c) contacting the mixture of step (b) with the cycloalkenone.
The term xe2x80x9cdiastereoselectivexe2x80x9d as used herein means that the desired isomer is formed predominantly, i.e. 50% or greater of the diastereomeric mixture.
The chiral 2,5-disubstituted-1,3-dioxolan-4-one is preferably a compound of formula (I): 
in which R1 is an optionally substituted hydrocarbyl group such as optionally substituted aryl, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl or optionally substituted C2-6alkynyl, where the substituents may be for example hydroxy, thiol, ethers, thioethers, primary, secondary and tertiary amines; Ra is a bulky group such as t-butyl, phenyl, diphenylmethyl, trityl, trichloromethyl, mesityl, or the like; the asterisk (*) indicates that the chiral center is of defined 3-dimensional configuration.
The base may be any that is capable of generating an enolate of the dioxolanone described above; examples of suitable bases include lithium diisopropylamide (LDA), lithium hexamethyldisilazide, lithium t-butoxide, sodium t-butoxide, DBU and tetramethyguanidine, and the like. Preferably a lithium base is used to generate the lithium enolate.
For the zinc-amine complex, the zinc component may be any zinc (II) compounds such as zinc chloride, zinc bromide, zinc iodide, zinc trifluoromethanesulfonate and the like. The amine component is an amine containing at least two nitrogen atoms separated by 2 to 6 atoms. Preferably the amine is a secondary or tertiary amine, more preferably a tertiary amine; suitable amines are, for example, of the formula (IV): 
wherein L is C2-6 alkylene or C2-6 alkenyl each of which may be optionally interrupted by a heteroatom selected from O, S and Nxe2x80x94Rc wherein Rc is H or C1-6 alkyl; each Rb is independently H or C1-4 alkyl or 2 Rbs together with the N to which they are attached form a 5- or 6-membered ring optionally containing an additional heteroatom selected from O, S and Nxe2x80x94Rc wherein Rc is H or C1-6alkyl. Examples of suitable amines are 4-[2-(dimethylamino)ethyl]morpholine; N,N-diethyl-Nxe2x80x2,Nxe2x80x2-dimethylethylenediamine; 1-[2(dimethylamino)ethyl]-4-methylpiperazine; N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine; 1-[2(dimethylamino)ethyl]pyrrolidine; 1-[(2-(dimethylamino)ethyl]piperidine; N,Nxe2x80x2,Nxe2x80x2-tetramethyl-1,3-propanediamine; N,N,Nxe2x80x2,Nxe2x80x2-tetramethyl-1,4-butanediamine; 1-[3-(dimethylamino)propyl]-4-methylpiperazine; 1-[3-(dimethylamino)propyl]-4-ethylpiperazine; 1-[3-(dimethylamino)propyl]piperidine; 1-[3-(dimethylamino)propyl]pyrrolidine; 1-[3-(dimethylamino)propyl]morpholine; N,N-bis-[2-(dimethylamino)ethyl]-N-methylamine; bis-[2-(dimethylamino)ethyl]ether. The preferred amine is selected from 4-[2-(dimethylamino)ethyl]morpholine; N,N-diethyl-Nxe2x80x2,Nxe2x80x2-dimethylethylenediamine; 1-[2(dimethylamino)ethyl]-4-methylpiperazine; N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine; 1-[2(dimethylamino)ethyl]pyrrolidine; and 1-[(2-(dimethylamino)ethyl]piperidine.
The cycloalkenone of the present process is a compound of formula (II): 
wherein n is 1, 2 or 3.
The novel process, in one embodiment, is illustrated in the following scheme: 
In the novel process, the product Michael adduct (III) is obtained as a mixture of diasteromers with the predominant diastereomer being determined by the configuration at the * carbon. For example, when the configuration at the * carbon is R, the predominant diastereomer of the Michael adduct has the R/R configuration at carbon atoms 1/2, and when the configuration at the * carbon is S, the predominant isomer has the S/S configuration at carbon atoms 1/2.
In the present process, the chiral dioxolanone is first treated with a base to generate the corresponding enolate. In one preferred embodiment the chiral dioxolane is a compound of formula (I) wherein R1 is phenyl and Ra is t-butyl. Preferably the base is lithium base such as lithium diisopropylamide and lithium hexamethyldisilazide. The base is preferably used in excess relative to the dioxolane, for example up to about 1.5 equivalents. The reaction is carried out under inert atmosphere at a temperature of xe2x88x9225xc2x0 C. or lower and in an aprotic organic solvent such as tetrahydrofuran, dimethoxyethane, toluene or other aromatic solvents, diethyl ether or methyl t-butyl ether, or a mixture thereof.
The resultant enolate is treated with a zinc-amine complex while maintaining the reaction temperature at below about xe2x88x9230xc2x0 C., for example from xe2x88x9245 to about xe2x88x9230xc2x0 C. The zinc-amine complex may be used in from about 0.2 to about 2 equivalents relative to the dioxolane. After about an hour, additional free amine is added to the mixture. The free amine is used in about two to about twenty equivalents relative to the dioxolane, preferably about two to about four equivalents. For the zinc-amine complex, the zinc component is preferably zinc chloride, and the amine is preferably selected from 4-[2-(dimethylamino)ethyl]morpholine; N,N-diethyl-Nxe2x80x2,Nxe2x80x2-dimethylethylenediamine; 1-[2(dimethylamino)ethyl]-4-methylpiperazine; N,N,Nxe2x80x2,Nxe2x80x2tetramethylethylenediamine; 1-[2(dimethylamino)ethyl]pyrrolidine; and 1-[(2-dimethylamino)ethyl]piperidine. The reaction mixture is maintained at about xe2x88x9220xc2x0 to about 0xc2x0 C. for about 30 minutes to about three hours. The mixture is then cooled to, for example, about xe2x88x9278xc2x0 C., and the cycloalkenone is added thereto. The cycloalkenone is added gradually such that the temperature of the reaction mixture does not exceed about xe2x88x9265xc2x0 C. for example between about xe2x88x9265 to xe2x88x9278xc2x0 C. The reaction is generally complete within about three hours.
In another aspect the present invention provides a diastereoselective process for the preparation of an xcex1-hydroxy acetic acid of the formula (V) or salts thereof 
wherein
n is 1, 2 or 3;
R1 is an optionally substituted hydrocarbyl group;
R2 and R3 are independently H, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, ORd, NRdRe; wherein Rd and Re are independently H, C1-6 alkyl, aryl, C3-7 cycloalkyl, C(O)Rd, or Rd, Re together with the N to which they are attached form a 5- or 6-membered ring optionally containing a heteroatom selected from O, S or NRc; Rc is H or C1-6alkyl; or
R2+R3 is oxo
which comprises
(a) contacting a chiral 2,5-disubstituted-1,3-dioxolan-4-one of formula (I) 
with a lithium base to provide the corresponding lithium enolate;
(b) contacting said enolate with a zinc-amine complex followed by addition of the free amine;
(c) contacting the mixture of step (b) with a 5- or 6-membered cycloalkenone of formula (II) 
to form a Michael adduct of formula III 
(d) optionally converting the keto group on the cycloalkane group of the Michael adduct (III) to R2 and R3 wherein R2 and R3 are other than oxo; and
(e) treating the product of step (c) or (d) with a base to provide the compound of formula (V).
Steps (a), (b) and (c) are discussed in detail hereinabove. In Step (d) the keto group on the cycloalkane group of the Michael adduct (III) may be transformed into other substituents such as hydroxy, amino, halogen, alkyl, alkenyl, and the like, or it may be removed to provide the unsubstituted cycloalkane. These chemical manipulations may be performed using well known chemical reactions such as hydrogenation, hydride reduction, Grinard reaction, Wittig reaction, reductive amination, halogenation; these and other suitable reactions are described in standard textbooks such as March, Advanced Organic Chemistry (3rd Edition, Wiley-Interscience).
More particularly, the keto group may be converted to gem-difluoro using fluorinating reagents such as DAST or NOBF4. In a more preferred method, difluorination is accomplished using bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor(trademark), Air Products, Allentown, Pa.). The difluorination using bis(2-methoxyethyl)aminosulfur trifluoride is carried out in an aprotic, nonpolar organic solvent, preferably non-ethereal solvent, or a mixture thereof, and preferably in the presence of a proton source such as water, alcohol, an organic or inorganic acid such as trifluoroacetic acid, or in the presence of a Lewis acid such as boron trifluoride etherate or gallium trichloride. The proton source or Lewis acid is present in about 5 to about 20 mole percent of the starting ketone. It has been found that the combination of trifluoroacetic acid or boron trifluoride etherate and toluene is particularly advantageous. The reaction is carried out at elevated temperature, e.g., from about 30 to about 60xc2x0 C. and the reaction is generally complete within 24 hours.
The Michael adduct or a keto-modified derivative thereof may be converted to the corresponding xcex1-hydroxyacetic acid (V) using base-induced hydrolysis. A base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate and the like may be used, and the reaction is carried out at elevated temperature of about 30 to about 60xc2x0 C. The acid (V) may be converted to an organic or inorganic base salt such as the dicyclohexylamine, benzylamine, diethylamine, lithium, sodium and potassium salts using conventional chemical techniques.
The xcex1-hydroxyacetic acid (V) may be used to couple with an amine of the formula (B) or salts thereof: 
(Rx is as defined in U.S. Pat. No. 5,948,792 as R2) to provide compounds of formula (A). The coupling of the acid of formula (V) and the amine of formula (B) may be carried out under conventional amide formation conditions. Thus, the reaction may be carried out in the presence of coupling agents such as a carbodiimide (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) and hydroxybenzotriazole. The acid may also be converted into an acylating equivalent, such as the corresponding acid chloride, and reacted with the amine compound in the presence of a base such as secondary and tertiary amines.